The candidate, a board certified pediatrician with a Ph.D. in molecular genetics, is completing a clinical genetics fellowship. He has a long-standing and continued interest in the etiology of human genetic diseases. In pursuit of these interests, he has sought relevant clinical and research training with a long-term goal of contributing to the understanding of the molecular basis of disease pathogenesis. This proposal provides a mechanism for achieving an immediate career goal of expanding the candidate's research experience to mouse genetics and utilization of this model system in the analysis and manipulation of mouse physiology. Applying this knowledge towards understanding the development of obesity will provide insight into the human disease. The purpose of this study is to determine the physiologic role of growth differentiation factor 3 (GDF-3) and its modification of the diet-induced obesity phenotype. Obesity is an increasing worldwide problem that is negatively impacting global health. GDF-3 is a member of the transforming growth factor beta superfamily of cytokines, many of which have critical roles in developmental and physiologic processes. Some also influence adipogenesis, and emerging evidence indicates a similar role for GDF-3. Expression levels are high in white adipose, and further up-regulated in response to high fat diet. Additionally, mice deficient in GDF-3 are protected from diet-induced obesity because of decreased adiposity. This phenotype will be investigated further in this proposal. Pathologic changes will be studied in white adipose, physiologic processes will be analyzed, and determinants of energy flux will be evaluated. GDF-3 expression in relevant tissues and hypothesized roles in the regulation of energy homeostasis, preadipocyte differentiation, and mature adipocyte functioning will be explored. Other genes important in these pathways will be investigated to characterize GDF-3's molecular relationships. These studies will provide valuable insight into adipogenesis and obesity, leading to a greater understanding of the underlying pathophysiology, and potentially resulting in pharmacological interventions to combat this disease. The environment in which this study will be performed is well-suited for facilitating the applicant's career development plan as the Department of Molecular and Human Genetics at the Baylor College of Medicine is renowned for its mouse genetics and interdisciplinary and interdepartmental collaborative atmosphere. Through a combination of supervised research and scientific interchange, the applicant will obtain the training necessary for a successful transition to an independent investigator. Brief Statement: Obesity is a significant medical problem with an increasingly negative impact on human health worldwide. Studies of growth differentiation factor 3 (GDF-3) will provide insight into the development of obesity, with the aim of leading to pharmacologic interventions to help combat this disease.